DCLK1

Official Full Name

doublecortin like kinase 1

Organism

Homo sapiens

GeneID

9201

Background

This gene encodes a member of the protein kinase superfamily and the doublecortin family. The protein encoded by this gene contains two N-terminal doublecortin domains, which bind microtubules and regulate microtubule polymerization, a C-terminal serine/threonine protein kinase domain, which shows substantial homology to Ca2+/calmodulin-dependent protein kinase, and a serine/proline-rich domain in between the doublecortin and the protein kinase domains, which mediates multiple protein-protein interactions. The microtubule-polymerizing activity of the encoded protein is independent of its protein kinase activity. The encoded protein is involved in several different cellular processes, including neuronal migration, retrograde transport, neuronal apoptosis and neurogenesis. This gene is up-regulated by brain-derived neurotrophic factor and associated with memory and general cognitive abilities. Multiple transcript variants generated by two alternative promoter usage and alternative splicing have been reported, but the full-length nature and biological validity of some variants have not been defined. These variants encode different isoforms, which are differentially expressed and have different kinase activities.[provided by RefSeq, Sep 2010]

Synonyms

CL1; DCLK; CLICK1; DCDC3A; DCAMKL1;

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Detailed Information

Doublecortin-like kinase 1 (DCLK1) is an evolutionarily conserved serine/threonine kinase that shares homology with the Xenopus laevis doublecortin protein (DCX), which is involved in brain development and neuronal migration. DCLK1 has been implicated in various cellular processes, including cell fate determination, neuronal migration, axon guidance, and synaptic plasticity.

Structure And Domain Organization of DCLK1

The DCLK1 gene is encoded by 21 exons and spans approximately 300 kb on chromosome 10q22.3. The protein consists of 561 amino acids and exhibits a modular structure, with several conserved domains. The N-terminal region contains a pleckstrin homology (PH) domain, followed by a doublecortin domain (DCX) and a calmodulin-binding domain (CaM-BD). The central region includes a kinase domain, while the C-terminal region contains a PDZ domain and a leucine-rich repeat (LRR) motif.

Function And Signaling Pathways of DCLK1

DCLK1 is involved in diverse signaling pathways and plays a crucial role in cellular processes such as cell migration, proliferation, and survival. The PH domain mediates the interaction of DCLK1 with phospholipid-rich membranes, promoting cell migration and invasion. The DCX domain interacts with microtubules and is responsible for the regulation of neuronal migration. The CaM-BD domain enables the interaction of DCLK1 with calmodulin, which modulates the kinase activity and cellular localization of the protein.

Figure 1. DCLK1 as a direct IKKβ regulator in inflammatory signaling.

The kinase domain of DCLK1 phosphorylates various substrates, including proteins involved in cell adhesion, cytoskeletal organization, and transcription factors. The phosphorylation of these substrates influences their activity and cellular function, leading to changes in cell behavior. The PDZ domain interacts with the C-terminal region of target proteins and is responsible for the localization of DCLK1 to specific cellular compartments. The LRR motif is involved in protein-protein interactions and plays a role in the recruitment of DCLK1 to sites of neuronal synapse formation.

Roles of DCLK1 in Development and Disease

DCLK1 is highly expressed during embryonic development and is involved in the formation and differentiation of the nervous system. In the adult central nervous system (CNS), DCLK1 is expressed in various neuronal subtypes and plays a role in synaptic plasticity and neuronal repair. Abnormal expression or function of DCLK1 has been implicated in several neurological disorders, including Alzheimer's disease, Parkinson's disease, and epilepsy.

In addition to its role in neurodevelopment and function, DCLK1 has been implicated in cancer development and progression. Overexpression of DCLK1 has been observed in various cancer types, including breast, colon, and glioblastoma, and is associated with increased cell proliferation, migration, and invasion. Furthermore, DCLK1 has been identified as a potential therapeutic target for the treatment of cancer and other diseases.

References:

Ferguson, Fleur M et al. "Discovery of a selective inhibitor of doublecortin like kinase 1." Nature chemical biology vol. 16,6 (2020): 635-643. doi:10.1038/s41589-020-0506-0
Luo, Wu et al. "Doublecortin-like kinase 1 activates NF-κB to induce inflammatory responses by binding directly to IKKβ." Cell death and differentiation vol. 30,5 (2023): 1184-1197. doi:10.1038/s41418-023-01147-8

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